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Patients with end-stage renal disease (ESRD) are at a higher mortality risk compared with the general population. Previous studies have described a relationship between mortality and patients with ESRD, but the data on standardized mortality ratio (SMR) corresponding to different causes of death in patients undergoing hemodialysis (HD) and peritoneal dialysis (PD) are limited. This study was designed as a nationwide population-based retrospective cohort study. Incident dialysis patients between January 2000 and December 2015 in Taiwan were included. Using data acquired from the Taiwan Death Registry, SMR values were calculated and compared with the overall survival. The results showed there were a total of 128,966 patients enrolled, including 117,376 incident HD patients and 11,590 incident PD patients. It was found that 75,297 patients (58.4%) died during the period of 2000–2017. The overall SMR was 5.21. The neoplasms SMR was 2.11; the endocrine, nutritional, metabolic, and immunity disorders SMR was 13.53; the circulatory system SMR was 4.31; the respiratory system SMR was 2.59; the digestive system SMR was 6.1; and the genitourinary system SMR was 27.22. Therefore, more attention should be paid to these diseases in clinical care.

Triple negative breast cancer (TNBC) is one of the leading causes of cancer death in the world and lacks an effective targeted therapy. G-protein-coupled receptor 161 (GPR161) has been demonstrated to perform the functional regulations on TNBC progression and might be a potential new target for TNBC therapy. This study showed the effects of bisdemethoxycurcumin (BDMC) on GPR161 regulation, indicating that BDMC effectively inhibited GPR161 expression and downregulated GPR161-driven signaling. BDMC showed the potent inhibitory effects on TNBC proliferation through suppressing GPR161-mediated mammalian target of rapamycin (mTOR)/70 kDa ribosomal protein S6 kinase (p70S6K) activation. Besides, in this study, we discover the mechanism of GPR161-driven TNBC metastasis, linking to GPR161-mediated twist-related protein 1 (Twist1)/matrix metallopeptidase 9 (MMP9) contributing to the epithelial-mesenchymal transition (EMT). BDMC effectively repressed GPR161-mediated TNBC metastasis via inhibiting Twist1/MMP9-induced EMT. The three-dimensional invasion assay also showed that BDMC significantly inhibited TNBC invasion. The combination treatment of BDMC and rapamycin enhanced the inhibition of TNBC proliferation and metastasis through increasing the blockage of mTOR activation. Furthermore, this study also observed that BDMC activated the caspase 3/9 signaling pathway to induce TNBC apoptosis. Therefore, BDMC could be applicable to anticancer therapy, especially targeting on the GPR161-driven cancer type.

Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) shows little or no toxicity in most normal cells and preferentially induces apoptosis in a variety of malignant cells. However, patients develop resistance to TRAIL, therefore, sensitizing agents that can sensitize the tumor cells to TRAIL-mediated apoptosis are necessary. In this study, we investigated the effect of 2-(3-hydroxyphenyl)-5-methylnaphthyridin-4-one (CSC-3436), an useful flavonoid, to overcome the TRAIL-resistant triple negative breast cancer (TNBC) cells. We found that CSC-3436 potentiated TRAIL-induced apoptosis in TRAIL-resistant TNBC cells and this correlated with the upregulation of death receptors (DR)-5 and down-regulation of decreased decoy receptor (DcR)-1 expression. When examined for its mechanism, we found that the decreased expression of anti-apoptotic proteins c-FLIPS/L, Bcl-Xl, Bcl-2, Survivin, and XIAP. CSC-3436 would increase the expression of Bax and promoted the cleavage of bid. In addition, the induction of DR5 by CSC-3436 was found to be dependent on the modulation of reactive oxygen species (ROS)/p38/C/EBP-homologous protein (CHOP) signaling pathways. Overall, our results indicated that CSC-3436 could potentiate the apoptotic effects of TRAIL through down-regulation of cell survival proteins and upregulation of DR5 via the ROS-mediated upregulation of CHOP protein.

Bladder cancer is the most common malignancy of the urinary tract and arising from the epithelial lining of the urinary bladder. Resistance to cytotoxic therapies is associated with overexpression of oncogenic proteins; including HER2, and Akt in chemotherapy resistance of bladder cancer. Various studies demonstrated that curcuminoids, the most important active phenolic compounds of turmeric (Curcuma longa), have anti-tumor activities in a wide range of human malignant cell lines. The aim of this study is to evaluate whether curcuminoids (curcumin, demethoxycurcumin (DMC), and bisdemethoxycurcumin) could repress the expression of HER2 in HER2-overexpressing bladder cancer cells. Among the test compounds, DMC significantly suppressed the expression of HER2, and preferentially inhibited cell proliferation and induced apoptosis in HER2-overexpressing bladder cancer cells. DMC decreases HER2 level through inhibiting the interaction of HER2 and Hsp90. Our study also indicated that DMC showed additive activity in combination with chemotherapeutic agents, including paclitaxel and cisplatin. These findings show that DMC should be developed further as a new antitumor drug candidate for treatment of HER2-overexpressing bladder cancer.

Fong-Yu Cheng,1 Yuan-Yow Chiou,2,3 Shih-Yuan Hung,4,5 Tsun-Mei Lin,6 Hao-Kuang Wang,7 Chi-Wei Lin,8 Hung-Hsiang Liou,9 Min-Yu Chang,5 Hsi-Hao Wang,5 Yi-Che Lee4,5,10 1Department of Chemistry, Chinese Culture University, Taipei, Taiwan; 2Department of Pediatrics, National Cheng Kung University Hospital, Tainan, Taiwan; 3Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 4School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan; 5Division of Nephrology, Department of Internal Medicine, E-DA Hospital, Kaohsiung, Taiwan; 6Department of Laboratory Medicine, E-DA Hospital, Kaohsiung, Taiwan; 7Department of Neurosurgery, E-DA Hospital, Kaohsiung, Taiwan; 8Department of Medical Education, E-DA Hospital, Kaohsiung, Taiwan; 9Division of Nephrology, Department of Internal Medicine, Hsin-Jen Hospital, New Taipei City, Taiwan; 10Division of Nephrology, Department of Internal Medicine, E-DA Dachang Hospital, Kaohsiung, TaiwanCorrespondence: Yi-Che LeeDivision of Nephrology, Department of Internal Medicine, E-DA Hospital/I-Shou University, No.1, Yida Road, Jiaosu Village, Yanchao District, Kaohsiung City, 82445, Taiwan, R.O.CTel +886-7-6150011 Ext 5121Email pipijer@gmail.comPurpose: Vitamin D3 is useful for the treatment of peritoneal dialysis (PD)-related peritoneal damage, but its side effects, such as hypercalcemia and vascular calcification, limit its applicability. Thus, we developed vitamin D-loaded magnetic nanoparticles (MNPs) and determined their therapeutic efficacy and side effects in vivo.Materials and Methods: Alginate-modified MNPs were combined with 1α, 25 (OH)2D3 to generate vitamin D-loaded nanoparticles. The particles were conjugated with an antibody against peritoneum-glycoprotein M6A (GPM6A). The particles’ ability to target the peritoneum was examined following intraperitoneal administration to mice and by monitoring their bio-distribution. We also established a PD animal model to determine the therapeutic and side effects of vitamin D-loaded MNPs in vivo.Results: Vitamin D-loaded MNPs targeted the peritoneum better than vitamin D3, and had the same therapeutic effect as vitamin D3 in ameliorating peritoneal fibrosis and functional deterioration in a PD animal model. Most importantly, the particles reduced the side effects of vitamin D3, such as hypercalcemia and body weight loss, in mice.Conclusion: Vitamin D-loaded MNPs could be an ideal future therapeutic option to treat PD-related peritoneal damage.Keywords: peritoneal dialysis, nanoparticles, vitamin D, fibrosis

Intracerebral hemorrhage (ICH) is a common and severe neurological disorder associated with high morbidity and mortality rates. Despite extensive research into its pathology, there are no clinically approved neuroprotective treatments for ICH. Increasing evidence has revealed that inflammatory responses mediate the pathophysiological processes of brain injury following ICH. Experimental ICH was induced by direct infusion of 100 μL fresh (non‐heparinized) autologous whole blood into the right basal ganglia of Sprague–Dawley rats at a constant rate (10 μL/min). The simvastatin group was administered simvastatin (15 mg/kg) and the combination therapy group was administered simvastatin (10 mg/kg) and ezetimibe (10 mg/kg). Magnetic resonance imaging (MRI), the forelimb use asymmetry test, the Morris water maze test, and two biomarkers were used to evaluate the effect of simvastatin and combination therapy. MRI imaging revealed that combination therapy resulted in significantly reduced perihematomal edema. Biomarker analyses revealed that both treatments led to significantly reduced endothelial inflammatory responses. The forelimb use asymmetry test revealed that both treatment groups had significantly improved neurological outcomes. The Morris water maze test revealed improved neurological function after combined therapy, which also led to less neuronal loss in the hippocampal CA1 region. In conclusion, simvastatin–ezetimibe combination therapy can improve neurological function, attenuate the endothelial inflammatory response and lead to less neuronal loss in the hippocampal CA1 region in a rat model of ICH.

Introduction: Stroke remains a leading cause of death worldwide. Stroke in young adults is an important issue, gaining extra attention in recent years. This study aims to investigate the mortality after stroke in young adults in Taiwan. Patients and methods: This is a registry- and population-based study in Taiwan of patients aged 20–50 years with first-ever stroke between 1999 and 2012, with follow-up until January 1, 2022. Patients and mortalities were identified through Taiwan National Health Insurance database. Results: The study population included 65,097 patients with stroke (mean age, 42.6 ± 6.6 years; 30.5% woman). There were 23,481 (36.1%) intracranial hemorrhage, 37,522 (57.6%) ischemic stroke, and 4094 (6.3%) stroke not otherwise specified. At the end of follow-up, a total of 18,248 deaths (28.0%) occurred during a median follow-up of 9.8 years (interquartile range, 6.4–13.7 years). Conclusion: Taiwan young adults who were 30-day survivors of first-ever stroke have significantly higher long-term mortality rates when compared to other population-based studies.

(1) Background: We aimed to determine whether physicians of different specialties perform differently in the monitoring, cost control, and prevention of acute outcomes in diabetes care. (2) Methods: Using data from the Health and Welfare Data Science Center, participants with newly diagnosed type 2 diabetes (n = 206,819) were classified into three cohorts based on their primary care physician during the first year of diagnosis: family medicine (FM), endocrinologist, and other internal medicine (IM). The three cohorts were matched in a pairwise manner (FM (n = 28,269) vs. IM (n = 28,269); FM (n = 23,407) vs. endocrinologist (n = 23,407); IM (n = 43,693) vs. endocrinologist (n = 43,693)) and evaluated for process indicators, expenditure on diabetes care, and incidence of acute complications (using subdistribution hazard ratio; sHR). (3) Results: Compared to the FM cohort, both the IM (sHR, 1.26; 95% CI, 1.08 to 1.47) and endocrinologist cohorts (sHR, 1.57; 95% CI, 1.38–1.78) had higher incidences of acute complications. The FM cohort incurred lower costs than the IM cohort (USD 487.41 vs. USD 507.67, p = 0.01) and expended less than half of the diabetes-related costs of the endocrinology cohort (USD 484.39 vs. USD 927.85, p < 0.001). (4) Conclusion: Family physicians may provide better care at a lower cost to newly diagnosed type 2 diabetes patients. Relatively higher costs incurred by other internists and endocrinologists in the process of diabetes care may be explained by the more frequent ordering of specialized tests.

Background: The purpose of this study was to evaluate the trends in adult spinal cases performed by E-Da hospital graduating neurological surgery residents, then comparing the case volumes against the national means in the US. Materials and Methods: The E-Da surgical case volumes were extracted using the hospital billing system for the years 2008–2017. These logs were coded according to the Accreditation Council for Graduate Medical Education guideline, providing a fair comparison against US national means. Linear regression analyses were conducted to identify changes in spinal categories. Finally, an unpaired student t-test was performed to compare E-Da case volumes to America's national means. Results: An average of 781.5 total spinal procedures were performed in the past 4 years of residency training for each of the four graduated E-Da neurosurgical residents, with the individual total caseload increasing by 38.07 cases each year (r2 = 0.40). The US national average was 427.72 spinal procedures for each of the 877 graduating residents, increasing by 19.96 cases every year (r2 = 0.95). E-Da has significantly more thoracic/lumbar instrumentation fusion procedures (mean 486.00 ± 90.27) and anterior cervical approach for decompression/stabilization and fusion procedures (mean 182.75 ± 42.91) than the US (means 145.95 ± 3.07 and 72.66 ± 4.62, respectively). The US has significantly more lumbar discectomy procedures (mean 125.70 ± 2.89), posterior cervical approach for decompression/stabilization and fusion procedures (mean 56.98 ± 3.73) and peripheral nerve procedures (mean 26.2 ± 0.79) than E-Da (means 64.5 ± 8.54, 39.75 ± 4.99, and 8.50 ± 5.07, respectively). Conclusion: Neurosurgical residents' surgical case exposures to different spinal categories were very different in E-Da and the US. Case entry logs provide valuable information nationally and internationally.

RationaleHaematoma growth is common early after intracerebral haemorrhage (ICH), and is a key determinant of outcome. Tranexamic acid, a widely available antifibrinolytic agent with an excellent safety profile, may reduce haematoma growth.Methods and designStopping intracerebral haemorrhage with tranexamic acid for hyperacute onset presentation including mobile stroke units (STOP-MSU) is a phase II double-blind, randomised, placebo-controlled, multicentre, international investigator-led clinical trial, conducted within the estimand statistical framework.HypothesisIn patients with spontaneous ICH, treatment with tranexamic acid within 2 hours of onset will reduce haematoma expansion compared with placebo.Sample size estimatesA sample size of 180 patients (90 in each arm) would be required to detect an absolute difference in the primary outcome of 20% (placebo 39% vs treatment 19%) under a two-tailed significance level of 0.05. An adaptive sample size re-estimation based on the outcomes of 144 patients will allow a possible increase to a prespecified maximum of 326 patients.InterventionParticipants will receive 1 g intravenous tranexamic acid over 10 min, followed by 1 g intravenous tranexamic acid over 8 hours; or matching placebo.Primary efficacy measureThe primary efficacy measure is the proportion of patients with haematoma growth by 24±6 hours, defined as either ≥33% relative increase or ≥6 mL absolute increase in haematoma volume between baseline and follow-up CT scan.DiscussionWe describe the rationale and protocol of STOP-MSU, a phase II trial of tranexamic acid in patients with ICH within 2 hours from onset, based in participating mobile stroke units and emergency departments.

Purpose Vitamin D is a novel potential therapeutic agent for peritoneal dialysis (PD)-related peritoneal fibrosis, but it can induce hypercalcemia and vascular calcification, which limits its applicability. In this study, we create nanotechnology-based drug delivery systems to investigate its therapeutics and side effects. Materials and methods 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [amino-(polyethylene glycol)2000] (DSPE-PEG) and L-α-phosphatidylcholine (PC), which packages with 1α,25(OH)2D3, were used to construct vitamin D nanoliposomes. To confirm the function and safety of vitamin D nanoliposomes, peritoneal mesothelial cells were treated with TGF-β1 and the reverse was attempted using vitamin D nanoliposomes. Antibodies (Ab) against the peritoneum-glycoprotein M6A (GPM6A) Ab were conjugated with vitamin D nanoliposomes. These particles were implanted into mice by intraperitoneal injection and the animals were monitored for the distribution and side effects induced by vitamin D. Results Vitamin D nanoliposomes were taken up by the mesothelial cells over time without cell toxicity and it also provided the same therapeutic effect in vitro. In vivo study, fluorescent imaging showed vitamin D nanoliposomes allow specific peritoneum target effect and also ameliorate vitamin D side effect. Conclusion Nanoliposomes vitamin D delivery systems for the prevention of PD-related peritoneal damage may be a potential clinical strategy in the future.

A therapeutic approach for promoting neuroprotection and brain functional regeneration after strokes is still lacking. Histone deacetylase 1 (HDAC1), which belongs to the histone deacetylase family, is involved in the transcriptional repression of cell-cycle-modulated genes and DNA damage repair during neurodegeneration. Our previous data showed that the protein level and enzymatic activity of HDAC1 are deregulated in stroke pathogenesis. A novel compound named 5104434 exhibits efficacy to selectively activate HDAC1 enzymatic function in neurodegeneration, but its potential in stroke therapy is still unknown. In this study, we adopted an induced rat model with cerebral ischemia using the vessel dilator endothelin-1 to evaluate the potential of compound 5104434. Our results indicated compound 5104434 selectively restored HDAC1 enzymatic activity after oxygen and glucose deprivation, preserved neurite morphology, and protected neurons from ischemic damage in vitro. In addition, compound 5104434 attenuated the infarct volume, neuronal loss, apoptosis, DNA damage, and DNA breaks in cerebral ischemia rats. It further ameliorated the behavioral outcomes of neuromuscular response, balance, forepaw strength, and functional recovery. Collectively, our data support the efficacy of compound 5104434 in stroke therapy and contend that it can be considered for clinical trial evaluation.

Yu-Ying Wu,1,2 I-Fan Lin,1,3 Po-Yuan Chen,1,2 Cheng-Kai Lin,1,2 Cheng-Chun Wu,1 Cheng-Loong Liang,1,2 Yi-Che Lee,1,4 Chi-Wei Lin,1,5 Wei-Leng Chin,1,5 Hao Kuang Wang1,2,6 1School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan; 2Department of Neurosurgery, E-Da Hospital, Kaohsiung, Taiwan; 3Division of Infectious Diseases, Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan; 4Department of Nephrology, E-Da Hospital, Kaohsiung, Taiwan; 5Department of Family Medicine, E-Da Hospital, Kaohsiung, Taiwan; 6Department of Neurosurgery, E-Da Cancer Hospital, Kaohsiung, TaiwanCorrespondence: Hao Kuang WangDepartment of Neurosurgery, E-Da Hospital/ I-Shou University, No. 1, Yida Road, Jiaosu Village, Yanchao District, Kaohsiung City, 82445, TaiwanTel +866-975106080Email ed101393@gmail.comBackground: Osteoporotic fractures are a significant cause of morbidity and mortality affecting population worldwide. All guidelines recommended vertebral fracture assessment by dual-energy X-ray absorptiometry (DXA). This study aimed at evaluation of any associated benefits of screening with DXA in patients who had received vertebroplasty in Taiwan.Methods: Data were obtained from the National Health Insurance Research Database (NHIRD) in Taiwan. We retrospectively compared the data of patients, who were admitted for vertebroplasty, whether they received DXA screening or not. The outcomes of interest were recurrence of spinal fracture and mortality during a follow-up period of 10 years.Results: From this Taiwan national database, the screening rate of osteoporosis in patient who received vertebroplasty was 11.7%. The mean age in the non-DXA screened cohort (n=32,986) was 74.03± 12.21 years (71.98% female). In the DXA screened cohort (n=4361), the mean age was 76.43± 9.19 years (79.91% female). During the 10-year follow-up period, after matching, non-DXA patients had significantly higher mortality rates than their DXA counterparts, which were 42.37% and 37.73% (p-value < 0.0001), respectively. The re-fracture rates between non-DXA and DXA patients were not significantly different at 17.26% and 16.89% (p-value = 0.1766), respectively.Conclusion: The rate of DXA screening before patients receiving vertebroplasty was extremely low, at 11.7%. Our results showed that DXA screening before vertebroplasty in spinal fractures patients had lower mortality. From this national retrospective cohort study, routine screening of osteoporosis in spinal fracture patients can lead to reduction in mortality.Keywords: osteoporosis, vertebroplasty, DXA, mortality

Hao-Kuang Wang,1,2 Jui-Sheng Chen,1,3,4 Chien-Yu Hsu,1 Yu-Ting Su,5 Tzu-Ching Sung,2 Cheng-Loong Liang,1,6 Aij-Lie Kwan,3,7 Cheng-Chun Wu6 1Department of Neurosurgery, E-DA Hospital, I-Shou University, Kaohsiung, Taiwan; 2School of Medicine for International Students, College of Medicine, I-Shou University, Kaohsiung, Taiwan; 3Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 4Department of Neurosurgery, E-Da Dachang Hospital, I-Shou University, Kaohsiung, Taiwan; 5Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 6School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan; 7Department of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung, TaiwanCorrespondence: Cheng-Chun WuSchool of Medicine, College of Medicine, I-Shou University, Kaohsiung, TaiwanTel +886-7-6151100-7961Fax +886-7-6155150Email chengchunwu@isu.edu.twIntroduction: Cerebral ischemia is a leading cause of disability and death worldwide. However, an effective therapeutic approach for the condition remains undiscovered. The previously proposed growth factor-based therapy has been inefficient due to its inability to pass through the blood–brain barrier. B355252, a newly developed small molecule, exhibited a potential neuroprotective effect in vivo. However, its exact efficacy in cerebral ischemia remains unclear.Methods: We adopt an endothelin-1 stereotaxic intracranial injection to induced cerebral ischemia in rat. We further conducted 2,3,5-triphenyltetrazolium chloride (TTC) staining, immunofluorescent staining, enzyme-linked immunosorbent assay (ELISA), and behavioral tests to evaluate the efficacy of B355252 in neuroprotection, anti-inflammation, and behavioral outcome improvements.Results: We identified that B355252 could protect ischemic neurons from neuronal loss by attenuating DNA damage, reducing ROS production and the LDH level, and preventing neuronal apoptosis. Moreover, inflammatory responses in astrocytic and microglial gliosis, as well as IL-1β and TNF-α levels, were ameliorated. Consequently, the behavioral outcomes of ischemic rats in neurologic responses and fore paw function recovery were improved.Discussion: Overall, our study verified the in vivo therapeutic potential of B355252. The study findings further support its application in the development of a therapeutic approach for stroke.Keywords: stroke, NGF, B355252, stroke, DNA damage, inflammation, mNSS, cylinder test

Objective: Stroke in young adults is uncommon, and the etiologies and risk factors of stroke in young adults differ from those in the older populations. Smoker’s paradox is an unexpected favorable outcome, and age difference was used to explain the association between smoking and the favorable functional outcome. This study aimed to investigate the existence of this phenomenon in young stroke patients.Methods: We analyzed a total of 9,460 young stroke cases registered in the nationwide stroke registry system of Taiwan between 2006 and 2016. Smoking criteria included having a past or current history of smoking more than 1 cigarette per day for more than 6 months. After matching for sex and age, a Cox model was used to compare complications, mortality and outcomes between smokers and non-smokers.Results: Smoking was associated with older age, higher comorbidities, and higher alcohol consumption. Smoking patients with NIHSS scores of 11–15 had a worse functional outcome (adjusted OR, 0.81; 95% CI, 0.76–0.87), and smoking cessation would substantially reverse those effects.Conclusion: The smoker’s paradox definitely does not exist, and therefore we continue to strongly advocate the importance of smoking cessation.

Cheng-Loong Liang,1,2 Shih-Wei Wang,1,3 Han-Jung Chen,1,2 Yu-Duan Tsai,1,2 Jui-Sheng Chen,1,2 Hao-Kuang Wang,1,2 Kuo-Wei Wang2,4 1Department of Neurosurgery, E-DA Hospital, Kaohsiung, Taiwan; 2School of Medicine, I-Shou University, Kaohsiung, Taiwan; 3Department of Rheumatology, E-DA Hospital, Kaohsiung, Taiwan; 4Department of Neurosurgery, E-Da Cancer Hospital, Kaohsiung, TaiwanCorrespondence: Kuo-Wei Wang Email wang11290713@hotmail.com.twBackground: After proper patient selection, anatomically correct pulsed radiofrequency of the lumbar facet joints provide long-term pain relief in a routine clinical setting. In the study, we performed an analysis of clinical and radiological predictive factors and provide the scientific basis for this promising modality.Methods: The study included 198 patients with lower back pain due to lumbar facet joint disease who underwent medial branch block and pulsed radiofrequency during the period 2015– 2019. According to the improvement in pain score, the patients were divided into good and poor outcome groups. Clinical and radiological data were collected and analyzed.Results: The multivariable analysis revealed the predictive factors, including lumbar lordosis, lower lumbar lordosis, pelvic tilt, the number of facet joints, old compression fracture with/without vertebroplasty, and post lumbar fusion procedures.Conclusion: With the results of this study, we demonstrated that the improved outcome after the surgery was related to lumbar lordosis, lower lumbar lordosis, pelvic tilt, the number of facet joints, old compression fracture with/without vertebroplasty, and the lumbar fusion procedures. Old compression fractures and lumbar fusion would change the radiological factors and cause refractory lumbar facet joint pain.Keywords: lumbar facet joint pain, pulsed radiofrequency, lumbar lordosis, lower lumbar lordosis, pelvic tilt angle, lumbar fusion

Aim:Diabetes-related cerebral small vessel disease (CSVD) causes neurological deficits. Patients with diabetes showed pericyte loss as a hallmark of retinopathy. Cerebral pericytes, which densely localize around brain capillaries, are quiescent stem cells regulating regeneration of brain and may have a role in CSVD development. This study investigated whether diabetes impairs ischemia-provoked dedifferentiation of pericytes.Methods:A murine high-fat diet (HFD)-induced diabetes model was used. After cerebral ischemia induction in the mice, pericytes were isolated and grown for a sphere formation assay.Results:The sphere counts from the HFD group were lower than those in the chow group. As the spheres formed, pericyte marker levels decreased and SOX2 levels increased gradually in the chow group, but not in the HFD group. Before sphere formation, pericytes from the HFD group showed high p21 levels. The use of a p21 inhibitor rescued the reduction of sphere counts in the HFD group. At cellular level, hyperglycemia-induced ROS increased the level of p21 in cerebral pericytes. The p21-SOX2 signaling was then activated after oxygen-glucose deprivation.Conclusion:HFD-induced diabetes compromises the stemness of cerebral pericytes by altering p21–SOX2 signaling. These results provide evidence supporting the role of pericytes in diabetes-related CSVD and subsequent cerebral dysfunction.

Supplemental material, sj-pdf-1-dvr-10.1177_1479164121990641 for Hyperglycemia compromises the ischemia-provoked dedifferentiation of cerebral pericytes through p21–SOX2 signaling in high-fat diet-induced murine model by Hao-Kuang Wang, Chih-Yuan Huang, Yun-Wen Chen and Yuan-Ting Sun in Diabetes & Vascular Disease Research

Cheng-Kai Lin,1,2 Po-Yuan Chen,1,2 Yu-ying Wu,1,2 Cheng-Chun Wu,1 Han-Jung Chen,1,2 Cheng-Loong Liang,1,2 Yi-Che Lee,1,3 Chi-Wei Lin,1,4 Chao-Ming Hung,1,5,* Hao-Kuang Wang1,2,6,* 1School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan; 2Department of Neurosurgery, E-Da Hospital, Kaohsiung, Taiwan; 3Department of Nephrology, E-Da Hospital, Kaohsiung, Taiwan; 4Department of Family Medicine, E-Da Hospital, Kaohsiung, Taiwan; 5Department of General Surgery, E-Da Cancer Hospital, Kaohsiung, Taiwan; 6Department of Neurosurgery, E-Da Cancer Hospital, Kaohsiung, Taiwan*These authors contributed equally to this workCorrespondence: Chao-Ming Hung; Hao-Kuang WangDepartment of Neurosurgery, E-Da Hospital/I-Shou University, No. 1, Yida Road, Jiaosu Village, Yanchao District, Kaohsiung City 82445, TaiwanTel +866-975106080Email ed100647@edah.org.tw; ed101393@gmail.comBackground: Statin treatment improves clinical outcomes in patients with ischemic strokes, although there is no evidence regarding the safety of statin therapy in patients with intracerebral hemorrhage (ICH). This study aimed at evaluating the effects of continuing statin treatment after ICH.Methods: Data were obtained from the National Health Insurance Research Database in Taiwan. We retrospectively compared the data of patients with and without statin exposure after ICH. The outcomes of interest were recurrence of hemorrhagic stroke and mortality during a follow-up period of 10 years.Results: During the 10-year follow-up period, the mortality rate was 32.73% in the statin group and 42.77% in the non-statin group. Statin therapy in patients with acute ICH with dyslipidemia can decrease mortality.Conclusion: Statin therapy reduced the risk of 10-year mortality in patients who experienced acute hemorrhagic stroke.Keywords: statin, hemorrhagic stroke, mortality

BACKGROUND Stroke has been recognized as one of the major causes of adult disability worldwide, and post-stroke dementia may affect up to one-third of stroke survivors. This condition could be prevented if we could recognize and treat it earlier. Acupuncture as a complementary treatment for stroke has been shown to be beneficial for subsequent post-stroke rehabilitation. Our study investigated if acupuncture served additional advantages to decreasing the incidence of post-stroke dementia. METHODS We provide a retrospective cohort study from Taiwan National Health Insurance Research Database. This study compared the incidence of post-stroke dementia between cohorts with and without acupuncture treatment by calculating adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of acupuncture associated with post-stroke dementia using Cox proportional hazard regressions. The study group was composed of 9,547 patients who received first hospitalization for the treatment of stroke between 2002 and 2004; of which, 47,735 comparison patients were defined as the control group. The two groups were followed-up until the diagnosis of dementia presented or until the end of 2007. RESULTS The adjusted HRs of developing dementia among patients with stroke was 4.705 times the average (range, 4.353–5.085), and the incidence of dementia was higher in males. The study group tended to have less incidence of all kinds of dementia after acupuncture treatment, and patients without stroke receiving acupuncture had a lower probability of dementia than those untreated during the follow-up period. CONCLUSIONS This study presents evidence that acupuncture serves as an effective and alternative procedure to lower the risk of post-stroke dementia and the overall incidence of dementia in Taiwanese population.

Background and Purpose— The observation that smokers with stroke could have better outcome than nonsmokers led to the term “smoking paradox.” The controversy of such a complex claim has not been fully settled, even though different case mix was noted. Analyses were conducted on 2 independent data sets to evaluate and determine whether such a paradox truly exists. Methods— Taiwan Stroke Registry with 88 925 stroke cases, and MJ cohort with 541 047 adults participating in a medical screening program with 1630 stroke deaths developed during 15 years of follow-up (1994–2008). Primary outcome for stroke registry was functional independence at 3 months by modified Rankin Scale score ≤2, for individuals classified by National Institutes of Health Stroke Scale score at admission. For MJ cohort, mortality risk by smoking status or by stroke history was assessed by hazard ratio. Results— A >11-year age difference in stroke incidence was found between smokers and nonsmokers, with a median age of 60.2 years for current smokers and 71.6 years for nonsmokers. For smokers, favorable outcome in mortality and in functional assessment in 3 months with modified Rankin Scale score ≤2 stratified by the National Institutes of Health Stroke Scale score was present but disappeared when age and sex were matched. Smokers without stroke history had a ≈2-fold increase in stroke deaths (2.05 for ischemic stroke and 1.53 for hemorrhagic stroke) but smokers with stroke history, 7.83-fold increase, overshadowing smoking risk. Quitting smoking at earlier age reversed or improved outcome. Conclusions— “The more you smoke, the earlier you stroke, and the longer sufferings you have to cope.” Smokers had 2-fold mortality from stroke but endured stroke disability 11 years longer. Quitting early reduced or reversed the harms.

Objective Overweight and hyperlipidemia, the two established risk factors for acute ischemic stroke, are paradoxically associated with favorable outcomes. The paradox may be resolved by the concept of protein energy wasting (PEW), in which total cholesterol level and body mass index are used as nutritional indexes for predicting outcomes of chronic kidney disease. Methods Among 12 271 people with acute ischemic stroke and chronic kidney disease, 2086 were defined as being at risk of PEW—with a body mass index Results Based on the propensity score, 2081 PEW participants were matched to the same number of non-PEW control participants. PEW was associated with a higher mortality risk at 3 mo (adjusted hazard ratio, 1.19; 95% confidence interval [CI], 1.02–1.42) and 1 y (adjusted hazard ratio, 1.33; 95% CI1.13–1.52). PEW was also associated with poor functional outcomes (modified Rankin Scale score >2) at 1 mo (adjusted odds ratio, 1.32; 95% CI, 1.08–1.61) and 3 mo (adjusted odds ratio, 1.27; 95% CI, 1.03–1.56). Conclusions According to the PEW-based assessment system, a modest decrease in body mass index and total cholesterol levels suggests malnutrition and is associated with adverse outcomes of acute ischemic stroke.

Using a database that enabled longitudinal follow-up, we assessed the cost, outcome, complications, and readmission rate of ruptured cerebral aneurysms repaired by surgical clipping and endovascular coiling.This study was a retrospective review of data from a series of patients who underwent surgical clipping or endovascular coiling of ruptured cerebral aneurysms between 1996 and 2013. The medical records and hospital cost data were all examined.A total of 7690 and 1380 cases were treated with clipping and coiling, respectively. Patients treated with clipping had more comorbidities and were older. The average total cost for endovascular coiling was $13,974.3, whereas the average total cost for surgical clipping was $16,581.7. Perioperative (30-day) mortality was 10.7% in patients with coiled aneurysms, compared with 12.6% in those with clipped aneurysms (P = 0.045). After 1 year of follow-up, clipping was associated with a significantly longer length of hospital stay (P0.001) and significantly higher total hospital costs (P0.001).In Taiwan, the total hospital costs for the surgical clipping of cerebral aneurysms were higher than for endovascular coiling, and the surgical results were associated with significant complications. We suggest that the indications for coiling might need to be expanded from the current standards dictated by the guidelines in Taiwan.

Background and aims Renal dysfunction is a potent risk factor for cardiovascular diseases, including stroke. This study aimed to evaluate the impact of admission estimated glomerular filtration rate (eGFR) levels on short-term (1-month) and long-term (1-year) mortality in patients with acute ischemic stroke. Methods From the Taiwan Stroke Registry data, we classified ischemic stroke patients, identified from April 2006 to December 2015, into 5 groups by eGFR at admission: ≥ 90, 60–89, 30–59, 15–29, and Results Among 52,732 ischemic stroke patients, 1480 died within one month. The 1-month mortality rate was over 5-fold greater in patients with eGFR Conclusions After acute ischemic stroke, patients with reduced eGFR are at elevated risks of short-term and long-term deaths in a graded relationship.

Cancer is a global issue in recent decade. Despite this alarming increase in the incidence of cancer, to date, whether the risk of developing cancer differs among peritoneal dialysis (PD) and hemodialysis (HD) patients is still uncertain. In this retrospective cohort study, data were obtained from the National Health Insurance Research Database of Taiwan, which provides coverage to almost 99% of the nation's population. After matching, a total of 4491 (or 3369) incident PD patients and 8982 (or 6738) incident HD patients between 2000 and 2009 were enrolled from the database. In addition, 22,455 (or 16,845) nondialysis patients were selected as a control group. The patients were monitored for the occurrence of cancer until 2010, and their data were analyzed using several different models. In general, the results showed that the risks of hepatocellular, kidney, bladder, extra kidney/bladder urinary tract, and thyroid cancers were higher in dialysis patients. We also compared the risk of cancer between two dialysis groups by using the HD patients as the reference group. The result showed that there is no significant different for each cancer risk between two dialysis groups. In conclusion, dialysis patients had a higher risk of certain types of cancer than those in the nonuremia group. However, there was no significant difference in the cancer risk between the two dialysis groups when compared directly.

Background: Duroplasty has been widely used in cranial surgery when primary closure is not possible. The goal is to protect the cerebrum and thereby ensure that complications were as few as possible. We reviewed a single-institution experience with a variety of dural substitutes in craniotomy and analyzed the risk factors for duroplasty-associated hemorrhagic complications. Patients and Methods: Patients who received dural replacement after craniotomy or craniectomy between July 2004 and June 2009 were enrolled into this study. Medical records were reviewed for diagnosis, procedure, and type of dural replacement. Clinical courses were reviewed for hemorrhagic complications, including subdural hematoma, extradural hematoma, and subarachnoid hemorrhage. Logistic regression models were used to analyzed the risk factors of duroplasty-associated hemorrhagic complications. Results: Two hundred and twelve patients were included in the study. Overall, the hemorrhagic complication rate was 4.7% (10 patients). Complications were seen for microporous polyester urethane, expanded polytetrafluoroethylene monolayer, polyester silicone, and Biomesh in 4.1%, 0%, and 38.5% of patients, respectively. Patients who received duroplasty with Biomesh had a higher hemorrhagic complication rate with the odds ratio of 24.75 (95% confidence interval, 4.33–141.41) in comparison of those with microporous polyester urethane group after adjusting for individual confounders. Conclusion: The increased risk of hemorrhagic complications associated with craniotomy is modified by choice of dural replacement. Our results could assist clinicians in their decision-making with respect to the optimal timing for synthetic dural substitutes in patients with tumor infiltration of the patient's dura, severe brain swelling in traumatic brain injury, or a result of shrinkage from exposure and electrocautery.

The aggregation and deposition of transactivation response DNA-binding protein 43 (TDP-43) in neurons and astrocytes is characteristic in a number of neurodegenerative diseases including Alzheimer's disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis. Nevertheless, the exact role of TDP-43 in astrocytes is unknown. Recently, TDP-43 was identified in neurons but not astrocytes after traumatic brain injury (TBI) in humans. In the present study, we evaluated TDP-43 expression and proteolysis in astrocytes in a rat model of TBI. We assessed TDP-43 fragment expression, astrocyte morphology, neuronal population numbers, and motor function after TBI with or without intracerebroventricular administration of a caspase-3 inhibitor. Motor dysfunction was observed after TBI in potential association astrocytic TDP-43 short fragment mislocalization and accumulation, astrogliosis, and neuronal loss. Notably, caspase-3 inhibition prevented these changes after TBI. Our findings suggest that TDP-43 proteolysis in astrocytes is related to astrogliosis and subsequent neuronal loss in TBI, and that TDP-43 may be an important therapeutic target for preventing motor dysfunction after TBI.

We investigated the impact of serum cholesterol levels on 30-day mortality after ischemic stroke in dialysis patients.From the Taiwan Stroke Registry data, we identified 46,770 ischemic stroke cases, including 1101 dialysis patients and 45,669 nondialysis patients from 2006 to 2013.Overall, the 30-day mortality was 1.46-fold greater in the dialysis group than in the nondialysis group (1.75 versus 1.20 per 1000 person-days). The mortality rates were 1.64, .62, 2.82, and 2.23 per 1000 person-days in dialysis patients with serum total cholesterol levels of 120 mg/dL, 120-159 mg/dL, 160-199 mg/dL, and ≥200 mg/dL, respectively. Compared to dialysis patients with serum total cholesterol levels of 120-159 mg/dL, the corresponding adjusted hazard ratios of mortality were 4.20 (95% confidence interval [CI] = 1.01-17.4), 8.06 (95% CI = 2.02-32.2), and 6.89 (95% CI = 1.59-29.8) for those with cholesterol levels of 120 mg/dL, 160-199 mg/dL, and ≥200 mg/dL, respectively.Dialysis patients with serum total cholesterol levels of ≥160 mg/dL or 120 mg/dL on admission are at an elevated hazard of 30-day mortality after ischemic stroke.

Background Medical radiation is considered a factor responsible for cataractogenesis. However, the incidence of this ophthalmologic complication resulting from gamma knife radiosurgery (GKRS) has not yet been reported. The present study aimed to determine the risk of cataractogenesis associated with radiation exposure from GKRS. Methods This study used information from a random sample of one million persons enrolled in the nationally representative Taiwan National Health Insurance Research Database. The GK group consisted of patients who underwent GKRS between 2000 and 2009. The non-GK group was composed of subjects who had never undergone GKRS, but who were matched with the case group for time of enrollment, age, sex, history of coronary artery disease, hypertension, and diabetes. Results There were 277 patients in the GK group and 2770 matched subjects in the non-GK group. The GK group had a higher overall incidence of cataracts (10.11% vs. 7.26%; crude hazard ratio [cHR], 1.59; 95% CI, 1.07–2.36; adjusted hazard ratio [aHR], 1.25; 95% CI, 0.82–1.90) than the non-GK group. Patients who had undergone computed tomography and/or cerebral angiography (CT/angio) studies had a higher risk of developing cataracts than those who did not (10.82% vs. 6.64%; cHR, 1.74; 95% CI, 1.31–2.30; aHR, 1.65; 95% CI, 1.22–2.23). The age group between 30 and 50 years had the highest risk of cataractogenesis in both the GK and CT/angio groups (cHR, 3.50; 95% CI, 1.58–7.72; aHR, 2.43; 95% CI, 1.02–5.81; cHR, 2.96; 95% CI, 1.47–5.99; aHR, 2.27; 95% CI, 1.05–4.93, respectively). Conclusions Radiation exposure due to GKRS and CT/angio study may be independently associated with increased risk of cataractogenesis. We suggest routine dosimetry measurement of eye lens and proper protection for patients with benign lesions during GKRS. Regular follow-up imaging studies should avoid the use of CT/angio, and particular care should be taken in the 30–50-year-old age group, due to their significantly increased risk of cataract formation.

STUDY OBJECTIVES: Peritoneal dialysis (PD) is a renal replacement therapy. One concern is whether patients on PD have a higher risk of sleep apnea (SA) due to intra-abdominal pressure increase and worsened ultrafiltration capacity. Despite this concern, to date, whether the risk of SA differs between PD, hemodialysis (HD), and groups without uremia is still uncertain. METHODS: In this retrospective cohort study, data were obtained from the National Health Insurance Research Database of Taiwan. This database enrolled almost all patients on dialysis in the country. A total of 7,645 incident patients on PD and 38,225 incident patients on HD were enrolled. In addition, 38,225 patients without uremia were selected as the comparison cohort. Individuals were monitored for the occurrence of SA until 2013. RESULTS: The results showed that patients on PD, regardless of sex, all had a higher risk of SA than non-dialysis groups. In contrast, the risk of SA in patients on HD was not significantly different from that of patients without uremia. We also compared the risk of SA between patients on PD and HD directly. The results showed that male patients on PD had a significantly higher risk of SA risk than male patients on HD. However, the risk of SA did not differ between female patients on PD and HD. CONCLUSIONS: Patients on PD should receive regular SA assessments and that an increased awareness and a higher index of suspicion for SA should be maintained in these patients, especially male patients. CITATION: Lee YC, Hung SY, Wang HK, Lin CW, Wang HH, Chang MY, Wu CF, Sung JM, Chiou YY, Lin SH. Male patients on peritoneal dialysis have a higher risk of sleep apnea. J Clin Sleep Med. 2019;15(7):937–945.

During a spinal cord injury (SCI), mechanical trauma rapidly leads to a blood-spinal cord barrier (BSB) disruption, neural cell damage, axonal damage, and demyelination, followed by a cascade of secondary inflammatory reactions. These inflammatory responses spread the damage to the neural cells and impair the recovery of neurological functions. In the present study, we evaluated the efficacy of simvastatin and a simvastatin-ezetimibe combination therapy in managing the endothelial inflammatory response in an SCI rat model. Adult male Sprague-Dawley rats were group-housed and SCI was induced by using the modified weight-drop method. The animals were divided into 4 groups: (1) sham group, laminectomy only (n=6); (2) no-treatment group, SCI without therapy (n=8); (3) simvastatin group (n=8), and (4) ezetimibe and simvastatin combination therapy group (n=8). A high dose (15 mg/kg) of simvastatin was given to the simvastatin group, and 10 mg/kg simvastatin and 10 mg/kg ezetimibe were given to the combination group. Neurological function was assessed using the Basso, Beattie, and Bresnahan locomotor scale score. Intercellular adhesion molecule-1 (ICAM-1) level was used as an SCI biomarker. ICAM-1 level was the highest at 72 hours after SCI in the no-treament group. The treatment groups showed significant reduction in ICAM-1 levels at 72 hours. The treatment groups, especially the combination treatment group, showed better neurological function scores. Simvastatin and simvastatin- ezetimibe all could improve the neurological function and attenuate the endothelial inflammatory response after spinal cord injury in rat.

Objective: Smokers with stroke were reported to have a better survival than nonsmokers, and this phenomenon was labeled as “smoking paradox”. This study is to assess its validity from a national stroke registry data. Methods: A total of 88,925 cases of stroke registered in the nationwide stroke registry system of Taiwan between 2006 and 2016, with 4,169 deaths, were analyzed. Age-specific mortality rate for current, ex- and non-smokers were calculated. NIHSS score (National Institutes of Health Stroke Scale) was measured at 3 months and 6 months Cox model was used to compare complications, mortality and outcomes between smoker and non-smoker ground. Results: Smokers constituted more than half of the men (55%) but only 5% of the women. The median age for current smokers was 60.2, for nonsmokers, 71.6, and for ex-smokers, 72.5. Smokers, with nearly 12 years younger than nonsmokers, had smaller mortality rate at younger age groups with fewer deaths, but much larger mortality after age 60, and doubled the mortality rate at the largest group after age 70. Smokers, who quit early, had similar outcome as nonsmokers. When age was controlled, current smokers had worse functional outcome (NIHSS) even at 3 months (adjusted OR, 1.08; 95% CI, 1.02-1.14). Conclusion: Smokers, but not ex-smokers, developed stroke 12 years younger than nonsmokers, an ominous sign for smokers. They had higher age-specific mortality rate and poorer outcome than nonsmokers. Quitting early nearly reversed the harms. Smoking paradox does not exist.

Kang Lu,1 Po-Chou Liliang,1 Hao-Kuang Wang,1 Jui-Sheng Chen,1 Te-Yuan Chen,1 Ruyi Huang,2 Han-Jung Chen1,3 1Department of Neurosurgery, E-Da Hospital, 2Department of Family Medicine, E-Da Hospital, 3Department of Neurosurgery, E-Da Cancer Hospital, College of Medicine, I-Shou University, Kaohsiung, Taiwan Background/objective: Internal disk disruption (IDD), an early event of lumbar disk degeneration, is the most common cause of low back pain. Since increased intradiskal pressure (IDP) is associated with symptoms and progression of disk degeneration, unloading a painful disk with an interspinous process device (IPD) is a rational treatment option. The goal of this study was to evaluate the effectiveness of dynamic stabilization with an IPD in the treatment of symptomatic IDD of the lumbar spine. Patients and methods: Patients with symptomatic IDD were treated with implantation of an IPD, the device for intervertebral assisted motion (DIAM). Diagnosis of IDD was based on typical MRI finding of posterior annular high-intensity zone and positive provocative test on discography. IDP was analyzed intraoperatively. Axial back and leg pain was evaluated with visual analog scale, functional status with Oswestry Disability Index, and final clinical outcomes with Odom criteria. Data from 34 patients followed up for at least 3years were collected. Results: DIAM implantation significantly reduced IDP (n=11, P

Background To determine the association of prior traumatic brain injury (TBI) with subsequent diagnosis of neurodegeneration disease. Methods All studies from 1980 to 2016 reporting TBI as a risk factor for diagnoses of interest were identified by searching PubMed, Embase, study references, and review articles. The data and study design were assessed by 2 investigators independently. A meta-analysis was performed by RevMan 5.3. Results There were 18 studies comprising 3,263,207 patients. Meta-analysis revealed a significant association of prior TBI with subsequent dementia. The pooled odds ratio (OR) for TBI on development of dementia, FTD and TDP-43 associated disease were 1.93 (95% CI 1.47–2.55, p